Liver Med23 ablation improves glucose and lipid metabolism and prevent diet-induced obesity
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE48966 | GEO | 2015/03/16
SECONDARY ACCESSION(S): PRJNA212436
REPOSITORIES: GEO
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2014-08-20 | E-GEOD-60527 | biostudies-arrayexpress
Project description:Insulin resistance represents a hallmark during the development of type 2 diabetes mellitus (T2D) and in the pathogenesis of obesity-associated disturbances of glucose and lipid metabolism 1,2,3. MicroRNA (miR)-dependent posttranscriptional gene silencing has recently been recognized to control gene expression in disease development and progression including that of insulin-resistant T2D. MiRs, whose deregulation alters hepatic insulin sensitivity include miR-143, miR-181 and miR-103/107. Here we report that expression of miR-802 is increased in liver of two obese mouse models and of obese human subjects. Inducible transgenic overexpression of miR-802 in mice causes impaired glucose tolerance and attenuates insulin sensitivity, while reduction of miR-802 expression improves glucose tolerance and insulin action. We identify Hnf1b as a target of miR-802-dependent silencing and shRNA-mediated reduction of Hnf1b in liver causes glucose intolerance, impairs insulin signaling and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Hnf1b improves insulin sensitivity in db/db mice. Thus, the present study defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism via targeting Hnf1b and assigns Hnf1b an unexpected role in the control of hepatic insulin sensitivity.
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Project description:Insulin integrates hepatic glucose and lipid metabolism, directing nutrients to storage as glycogen and triglyceride. In type 2 diabetes, levels of the former are low and the latter are exaggerated, posing a pathophysiologic and therapeutic conundrum. A branching model1 of insulin signaling, with FoxO1 presiding over glucose production2-5 and Srebp–1c regulating lipogenesis,6-8 provides a potential explanation. Here we illustrate an alternative mechanism that integrates glucose production and lipogenesis under the unifying control of FoxO. Liver–specific ablation of three FoxOs (L–FoxO1,3,4) prevents the induction of glucose–6–phosphatase and the repression of glucokinase during fasting, thus increasing lipogenesis at the expense of glucose production. We document a similar pattern in the early phases of diet-induced insulin resistance, and propose that FoxOs are required to enable the liver to direct nutritionally derived carbons to glucose vs. lipid metabolism. Our data underscore the heterogeneity of hepatic insulin resistance during progression from the metabolic syndrome to overt diabetes, and the conceptual challenge of designing therapies that curtail glucose production without promoting hepatic lipid accumulation. We used microarrays to detail the change of gene expression in liver after knocking out FoxO1,3 and 4.
2014-08-20 | GSE60527 | GEO
Project description:Insulin resistance represents a hallmark during the development of type 2 diabetes mellitus (T2D) and in the pathogenesis of obesity-associated disturbances of glucose and lipid metabolism 1,2,3. MicroRNA (miR)-dependent posttranscriptional gene silencing has recently been recognized to control gene expression in disease development and progression including that of insulin-resistant T2D. MiRs, whose deregulation alters hepatic insulin sensitivity include miR-143, miR-181 and miR-103/107. Here we report that expression of miR-802 is increased in liver of two obese mouse models and of obese human subjects. Inducible transgenic overexpression of miR-802 in mice causes impaired glucose tolerance and attenuates insulin sensitivity, while reduction of miR-802 expression improves glucose tolerance and insulin action. We identify Tcf2 as a target of miR-802-dependent silencing and shRNA-mediated reduction of Tcf2 in liver causes glucose intolerance, impairs insulin signaling and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Tcf2 improves insulin sensitivity in db/db mice. Thus, the present study defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism via targeting Tcf2 and assigns Tcf2 an unexpected role in the control of hepatic insulin sensitivity. Adenoviruses (Ad5) encoding either GFP (Ad-Ctrl 1-3) or shTcf2 (Ad-shTcf2 1-4) were injected into the tail vein of C57BL/6 mice at 1x10E10 viral particles (VP) per gram bodyweight. Biotin-labeled cDNA was synthesized using GeneChip Whole Transcript Sense Labeling Assay (Affymetrix) according to vendorM-bM-^@M-^Ys instructions. After fragmentation, cDNAs were hybridized for 17h at 45M-BM-0C on Affymetrix Mouse Gene 1.0 ST Arrays. The Arrays were washed and stained in the GeneChip Fluidics Station 450 and scanned on a GeneChip Scanner 3000 7G (Affymetrix). Data intensities were log transformed and normalized with a quantile normalization method using Affymetrix Power Tools. Differentially expressed genes were identified according to statistical evidence indicated by Student's t-test and fold change statistics
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2020-08-21 | PXD015767 | Pride
Project description:Analysis of glucose and Lipid metabolism in male and female offspring after protein restriction of the mother Male offspring showed features of metabolic syndrome after receiving a high fat diet, regardless of the diet of the dam. Glucose and lipid metabolism in male offspring was unaltered. Insulin sensitivity and hepatic fatty acid storage in female offspring of low-protein-fed dams changed in such a way that it resembled the male pattern of insulin sensitivity and hepatic fatty acid storage. Microarray analysis on hepatic gene expression patterns confirmed these findings. We therefore conclude that in mice, maternal protein restriction does not change the response of glucose and fatty acid metabolism to a high fat diet in male offspring, but does program metabolism in female offspring in such a way that it resembles male metabolism. Our findings might have implications for potential future gender-specific treatment of the features of metabolic diseases. Total RNA obtained from liver (16 samples per gender) were compared in the different groups. In total, 4 groups per gender, each group consisting of 4 biological replicates.
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Research is published:
http://www.nature.com/ncomms/2015/150512/ncomms8079/full/ncomms8079.html
2015-06-10 | ST000198 | MetabolomicsWorkbench
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